Estrogen is a critical hormone in the human body because it regulates the growth, development and[unreadable] homeostasis of numerous tissues, including the regulation of mammalian reproduction and breast function,[unreadable] the central nervous and immune systems, skeletal physiology and vascular function. Our long-term goal is[unreadable] to elucidate the role of a novel intracellular, 7-transmembrane spanning, G protein-coupled estrogen receptor[unreadable] (GPR30) that we propose functions alongside the traditional estrogen receptor (ER) to regulate physiological[unreadable] responsiveness to estrogen. The specific hypothesis is that signaling through GPR30 regulates uterine[unreadable] function and cancer development. We base this hypothesis on our recent observations that 1) GPR30[unreadable] represents a functional, estrogen-binding G protein-coupled receptor (GPCR), 2) GPR30 activates novel[unreadable] nuclear phosphatidylinositol signaling pathways and 3) GPR30 is specifically expressed in uterine glandular[unreadable] epithelium and overexpressed in endometrial cancer. The specific aims are:[unreadable] 1. Characterize estrogen-mediated cellular activation by GPR30. We will compare cellular signaling initiated[unreadable] by GPR30 and traditional ERs, stimulated by estrogen as well as estrogen analogs, and determine the[unreadable] effects of the clinically used kinase inhibitors Iressa and Lapatinib.[unreadable] 2. Animal models of GPR30 function in uterine biology and neoplasia. We will determine the developmental[unreadable] regulation of GPR30 in the normal and neoplastic mouse uterus. Using GPR30 knockout mice, we will[unreadable] determine the role of GPR30 in estrogen-dependent signaling in the uterus and how this regulates[unreadable] endometrial tumor development.[unreadable] 3. Evaluation of GPR30 expression in human endometrial cancer. We will investigate the role of GPR30 as[unreadable] a novel biomarker predictive of grade, stage and adverse outcome in intermediate and high-risk endometrial[unreadable] cancer.[unreadable] Characterizing the functions of this novel estrogen receptor in conjunction with translational clinical trials[unreadable] will contribute to our understanding of estrogen-induced growth and proliferation in the neoplastic uterus,[unreadable] leading to the development of GPR30 as a novel biomarker and as a target for diagnostic and therapeutic[unreadable] development.